Di-guanyl hydrazones



'2 nitrogen atoms are incorporated into a ring. In the formula, the phenyl nuclei may also be submethane-4,4-di-aldehyde DI-GUANYL RAZONES Werner Meiser and Gerhard Domagk, Wuppertal-Elberfeld, Germany, assignors to Seheniey Industries, Inc., New York, N. Y., a corporation of Delaware No Drawing. Application March 25, 1954, Serial N0. 418,768

Claims priority, application Germany March 30, 1953 2 Claims. Cl. 260-564) X Y-NH-N=C =N NH-Y in which R is hydrogen or an alkyl radical; X is a direct linkage or a bridging member having up to about 12 atoms as, for example, oxygen, an S radical, i. e.

v a. sulfonyl radical, an ORO- radical in which R is an alkylene radical, sulfur, an imino radical, an alkyl radical which may, for example, contain hetero atoms such as oxygen, sulfur or imino radicals; and Y is a guanyl radical. The term guanyl radical is intended to include unsubstituted guanyl radicals and substituted guanyl radicals in which 1 to 3 of the hydrogen atoms are substituted with alkyl or aryl radicals. The term is also intended to include guanyl radicals in which the heterocyclic stituted. The

i C=NN H-Y group may be at the 2, 3, 4, 5 or 6 position, i. e. the compounds may be ortho, meta or para compounds.

These new compounds have been found to exhibit an extremely high bactericidal activity and have been found in which R and X are as described above.

The di-aldehydes and di-ketones employed in the condensation reaction may be prepared in various manners depending upon the nature of the bridging member X. Thus, for example, di-phenyl-4,4'di-aldehyde, di-phenyl ether-4,4'-di-aldehyde, di-phenyl thio-ether 4,4 di-aldehyde, 4,4'-di-aldehydo-di-phenyl sulfone and di-phenyl may be obtained from the respective di-methyl compounds by oxidation or through the w tetrabromo compounds as described in the literature.

Di-aldehydes and di-ketones containing methylene groups which are partially substituted by hetero atoms such as oxygen, sulfur or imino radicals are easily obtainable by condensing hydroxy benzaldehydes or hydroxy benzoketones or the corresponding thioor aminocompounds with alkyl di-halides in the presence of alkali metal hydroxides. This reaction in connection with 4-hydroxybenzaldehyde and 1,3 dibromopropane may be represented as follows:

Two mols of the amino guanidine are condensed with a mol of the di-aldehyde or di-ketone. The amino guanidines may be unsubstituted or may be substituted in any manner provided that the hydrazino group remains intact. One to three hydrogen atoms of the amino guanidine which are not attached to the hydrazino group may be substituted by alkyl or aryl radicals. Thus, for example, alkyl, di-alkyl, tri-alkyl amino guanidines may be used. In addition, products containing alkyl groups which are interrupted by hetero atoms or carry further substituents may be used. The amino guanidines may also contain 2 nitrogen atoms of the guanidine configuration incorporated in a heterocyclic ring as, for example, 2-hydrazino-2-imidazoline of the formula:

H2CN

20NHNH; 5 1/ H2CNH Or a Z-hydrazino-1,4,5,6-tetrahydropyrimidine of the formula:

As examples of aromatic amino guanidines which may be used there may be mentioned mono-, diand triarylamino guanidines containing a free hydrazino, i. e. -NHNH group as, for example, phenylor di-phenyl aminoguanidine. The phenyl nucleus of these aminoguanidines may carry further substituents. In addition, amino guanidines which are substituted by mixed aliphatic aromatic radicals such as N-ethyl-N-phenyl amino guanidine containing a free hydrazino group may be used. The aminoguanidine may also contain a heterocyclic substituent provided that the -NH-NH remains intact.

These aminoguanidines are, for the most part, described in the literature or may easily be obtained according to conventional methods as, for example, by the reduction of nitro guanidines or by the reaction of isothiourea salts and hydrazine. These amino guanidines may also be obtained by reaction of S-alkylthiosemicarbazide compounds and amines; by the addition reaction of hydrazine and cyanamides or by the desulfurization of thioureas in the presence of hydrazine.

For the reaction, 2 mols of the same or a different amino guanidine may be reacted with the di-ketone or dialdehyde. The hydrazino group enters into a condensation reaction with the carbonyl group of the di-aldehydes or di-ketones splitting off water.

The condensation. reaction is preferably effected in an alcoholic or aqueous alcoholic solution or in a mixture of water and a water soluble solvent such as dimethylformamide and dioxane. The reaction proceeds easily if the compounds are in the form of their salts.

.3 4 The condensation is preferably effected in the presence Example 2 of a small excess of acid though the same may alsobe performed in an alkaline medium. Thirty-one and two-tenths grams of p,p'-dialdehydo- An alternative .methodior the, synthesis.of.the.com- 1,5-diPheI1oXY Poniano P p from pounds,in accor,dance Wilththeiinvention,consistsofrfirst P- Y Y bonlaidohydo and L 'P in p d i corresponding thiosemicarbazones d, the presence of alkali) are dissolved in 250 cc. of warm th ft ti these thiosemicar bazone s i h alcohol and reacted with 22 'grams of aminoguanidine vmonia or aniinesin vthe.presencesof'heavy metaLsalts. hydrochloride in 25 of Water With the addition o It is also possible to'first produce the corresponding hydracc. :of concentrated hydrochloric acid. After a v olent zon sandtreatlthesame with cyanamides. 10 :reaction, the dihydrochloride'having a M. P. of 226 C. Alternativly, the new compounds may be prgduced begins to crystallize after standing for some time at a by condensing aminoguanidines and 'benzaldehydes moderately-raised temperature, as deSCI'lbCd in Example 1. benzoketones and linking 2 mols of'theresulting guanyl- The Crystals are isolated and'tho base is P p thorohydrazones with:aibridging member if gsuch is desired. f om y dissolution in about liters of warm water Thus, for example, p-bromobenzaldehyde may be conand Precipitation With ammoniay recrystallizins'from densed with aminoguanidine to yield the guanylhydrazone dilute methanol the di-gllanyi y zo 0f of p-bromobenzaldehyde which may be converted into y -P yP is obtained in fine White theqpguanyl u itphenyl dialdehyde by .crystals having a decomposition pointof 240 C. ,The

nuclear linkage. compound has the followingformula:

H;NC-NH-N=CH-0Om(CHi) OH OCH=NNHfiNH,

INH

It is also:possibleito react thetcondensation products The same compound is obtained by dissolving 5.7 10f :p-hydroxybenzaldehyde and .an :aminoguanidine with grams of p-hydroxybenzaldehydeguanyl hydrazone base :aldiehalogenoalkane such :as a di bromo alkane in the (prepared according to Annalen 302, page 304) in 50 cc. presence of an alkali'metal hydroxide thusforming the ofiabsolute alcohol, reacting the same with asolutiqn \new condensatiomproducts in-accordance with the inof sodium ethoxide formed from 0.7 gram of ,sodium -vention. in 22 cc. of absolute alcohol and boiling with 3.5 grams lThe saltsof themew compounds with-strongacids are, of 1,5-dibromo-n-pentane for 48 hours. After p uring for the most -part, diflicultly solublein cold water and 'on ice water with the addition of some ammonia, the relatively easily soluble in hot-water. They readily yield reaction product is recrystallized from methanol. free bases upon .reaction with alkali metal hydroxides Itis further possible to produce the same substance or with ammonia. The newtcompounds are colorless, from the bis-thiosemicarbazone of p,p'-dialdehydo-l-,5.-.difinely crystallized compounds-whichyield readily soluble ;.phenoxypentane (M. P. 210 C.) by reaction with amgsalts with:.organiczacids.'as, for.example, acetic acid and monia and lead hydroxide in alcoholic suspension.

lactic acid. 40

The following examples are-. given by way of illustration and ot limit ti Fourteen andtwo tenths grams of p,p-,dialdehydo- 1,3- vdiphenoxy propane are dissolved in 380 cc. of ,wfarm alcohol and reacted with 19.7 grams of isopropyhflflliflo Fourteen and two tenths grams of p,p'-dialdehydo-1,3- guanidine-hydrobromide (M. P. 112 0.; prepared from diphenoxypropane (M. P. 126 C.; prepared from 4-hy- S-ethylisopropyl-thiourea-hydrobromide and hydrazine) in Example 3 Example 1 droxybenzaldehyde'and =1,3-dibromopropane in .thepres- 20 cc. of water with the addition of some concentrated -enceof, alkali) are dissolved-in -380-cc. of warm alcohol .nitric acid. .After prolongedstanding with gentlezheatand a :solu'tion of 11 grams of amino guanidinehydroing, the mixture is poured; into liiliter of ;water-..with:the chloride, 15'cc."of"-w ater and 5;cc.-of,concentrated hydro- ,addition,ofsome-ammonia. The precipitatedabase;istsucchloricacid is'added. 'The.sol ution is left standing at -tionfiltered, dissolved inammonia andthe dihydrochloride '80 C. for"2- 3I"hours "whereupon crystallization be- .of the di-guanyl-isopropyhhydrazone of the above (ll-aldegins. -After-'cooling,1the crystals of the dihydrochloride hyde-isprecipitated withahydrochloricacid inthe fcrm -of'theM."P.240 Guam-isolated. Bydissolutionin' hot .ofanoil. ,The salt, crystallizes;after.decanting, washing -waterandiprecipitation-with ammonia, the 4,4'e'diguanyl with water and:treati ng with ethyl acetate. The'comhydrazoneofthefabovealdehyde is obtained as aJbase. :po,und has ;the followlngxformulaz After boiling once for a short time withsome acetic Example 4 acid, the condensation product is obtainedin the.form Fourteen and two'tenths grams of p,p'dialdehydo-1,3- of yellowish-white crystals,having a M.,.P. ,cf,. 226.,C. diphenoxypropane are dissolved in 380 cc. of warm alco- The compound has the following formula: hol and reacted-with 18.1 grams ,of, 2-hydrazino-2.-imida- The-condensation'productcan also'be obtainedifrom 'zoline hydrobromide (M. P. .186,C.;;p12eparedjrqmg 2- ""the bis-thiosemicarbazone of the above dialdehyde (deethylmercaptoQ-imidazoline ,hydrobromide and ,hgd -acomposition point 220 C.) by reaction with ammonia v zine) .i.n 18. cc. of ,water withdthe addition of .5 ,cc. bfihyandleadroxideinanalcoholic suspension. idrobrotnic .acid. After standing on 11 w m for I name one .hour, the di-hydrobromide crystallizes and is isolated; M. P. 302 C. By dissolution in water and treatment with ammonia and water, the di-imidazolino-hydrazone base of the above di-aldehyde is obtained; after recrystallizing from ethanohthe base is obtained in white crystals having a M. P. of 226 C. The compound has the following formula:

Example 5 Example 6 Two and eighty four one hundredths grams of p,p'-di-' aldehydo-l,3-diphenoxy-propane are dissolved in 75 cc.

of Warm alcohol and reacted with 4.6 grams of phenyl- 35 aminoguanidine hydrobromide (N amino N -phenylguanidinehydrobromide) (M. P. 111 C.; prepared from S-ethyl N phenylisothiourea hydrobromide and hydrazine) in 10 cc. of Water and 2 cc..of hy-drobromic acid. After standing for two hours with gentle heating, the mixture is concentrated and cooled. The precipitated dihydrobromide is stirred with concentrated ammonia water and suction filtered. The base is precipitated once more from acetic acid solution with ammonia. The nearly insoluble base of the p,p'-diphenylguanylhydrazone of 4.5

the above di-aldehyde crystallizes from ethyl acetate in yellowish crystals having a decomposition point of 230 C. The compound has the following formula:

.hydrolysis) in 100 cc. of alcohol are reacted grams of aminoguanidinehydrochloride in 11 cc. of water with the additionof cc. of concentrated hydrochloric acid. After standing on a Water bath for 3 hours, the mixture is evaporated in vacuo. The residue is dissolved in a larger quantity of water and precipitated with ammonia. After recrystallizing from methanol and water,

N CHZ the base of the di-guanyl-hydrazone of di-phenyl ether- 4,4'-di-aldehyde is obtained in white crystals having a decomposition point of 257 C. The compound has the following formula:

Example 9 Twenty one grams of di-phenyl-4,4-di-aldehyde (4,4 diformyl di-phenyl) (prepared from 4,4'-di-methyl di- 5 phenyl by oxidation with chromic acid in a mixture of NH-CH:

glacial acetic acid and acetic anhydride) are dissolved in 400 cc. of warm alcohol and reacted with 28 grams of aminoguanidine carbonate in 53 cc. of 4N-hydrochloric acid. After standing on the water bath for 3 hours and cooling the di-hydrochloride of the di-guanyl-hydrazone of di-phenyl-4,4'-di-aldehyde is suction filtered and washed. The compound has the following formula:

Example Twenty seven and four tenths grams of 4,4'-di-aldehydo-di-phenylsulfone (prepared according to Beilstein, vol. 8, page 84) in 400 cc. of alcohol are reacted with 22 grams of aminoguanidinehydrochloride in water and some hydrochloric acid. After standing on a water bath the Example 7 Sixteen and three tenths grams of p,p'-dialdehydo-1,6- diphenoxyhexane are dissolved in 120 cc. of warm alcohol and reacted with 11.1 grams of aminoguanidine-hydrochloride in 11 cc. of Water with the addition of 5 cc. of

concentrated hydrochloric acid. The mixture is placedon a Water bath and crystallization soon commences. After standing for two hours with gentle heating, the mixture is cooled and the dihydrochloride having a M. P. of 230 C. is isolated. The base of the di-guanyl-hydrazone of the above di-aldehycle is obtained therefrom in the- I usual manner and has a M. P. of 242 C. The compound has the following formula:

Example 8 Eleven and three tenths grams of diphenyl ether-4,4- di-aldehyde (4.4-diformyl di-phenyl oxide) (prepared from 4.4-dimethyldi-phenyl-ether by tetrabromination and for 3 hours, the di-hydrochloride of the di-guanylhydrazone begins to precipitate in colorless crystals. The com- 55 pound has the following formula:

This compound may also be prepared from the bis-thiesemicarbazone of 4,4'-di-aldehydo di-phenylsulfone with alcoholic ammonia and lead hydroxide.

Example 11 Eighteen and four tenths grams of p,p'-di-propionyl- S-di-phenoxypentane (M. P. 110 C.; prepared from p-hydroxypropiophenon'e and 1,5-di-bromo-n-pentane) in 200 cc. of alcohol are reacted with 14 grams of aminoguanidine carbonate in 43 cc. of 2.44N-hydrochloric acid.

After standing for a-short time "on a water bath, the a1 cohol is substantially evaporated and the residual solution is poured into about 1 liter of water with the addition of ammonia. After filtering and boiling with absolute alcohol, the base is obtained as white crystals having a 'M. "P. of 220 C Another quantity of this compound crystallizes from the alcohol. The compound has the following formula:

NH on,

Example '12 p Hydroxybenzaldehyde di niethylguanyl hydrazone (M. P. 300 C.; prepared from p-hydroxybenzaldehyde and N -amino-N -di-methyl guanidine hydrobrorm'de, M. P. 212 C.) are suspended in 200 cc. of alcohol and reacted with a solutionof sodium ethoxide formed from 1.93 grams of sodium in 60 cc. of alcohol. After addition of 4.8 grams of -1,5-di bromo-n-pentane, the mixture is heated to a boil for 48 hours. After cooling, the mixture is poured into 1' liter of ice water and suction filtered. The di-methyl-guanylhydrazone of p,p,-di-aldehydo-l,S-diphenoxypentane is obtained as white crystals having a M. P. of 175 C. by recrystallizing from methanol and water. The ,compound has the following formula;

228 C. is obtained as white crystals. The compound has t fiq ow a fera -a e;

li ll g I 5 H NH I =NH C=NH N NB:

Example 15 Seven grams of rn,m-di-aldehydo-1,5-di-phenoxypentane (prepared from rn-hydroxybenzaldehyde and 1,5-

,we.).sa aNaaseqa-gorc noa):emoQwnmwe-g-aee Example .13

Twenty five and eight tenths grams of o,o'-di-aldehydol,5-diphenoxypentane (melting point 79 C.; prepared from.o,- hydrq? y :benzaldehyde and 1 idi-bromo-n-pentane i t P es n .of an alka m a h d xide) a e di solved in 1-60-cc.;o f warm ,alcohol and reacted with 18.2 ac e-m o a inqs anidin h d ochl rid in 9 water wit t h ddit on of 9 0 9! $@t y ochloric acid. After heating at about 80 C. for three hours, the mixture is distilled in vacuo. The residue is dissolved in about 1 liter of-hot water and precipitated with ammonia. By recrystallizing from dilute alcohol, the di-guanylhydrazine of 2,2-dialdehyde-1,S-di-phe- 'noxypentane is obtained as white-crystals having amelting point of 209 .C. The compound has the following formula:

Example 14 dibromo-n-pentane in the presence of an alkali metal hydroxide) are dissolved in 25 cc. of dry ethanol and reacted with 6 grams of amino-guanidine hydrochloride in 6 cc. of water with the addition of '2 cc. of concentrated hydrochloric acid. After heating at -80 C. for about -3 hours, the liquid portion is distilled off in vacuo. The residue is dissolved in hot water and precipitated with ammonia. 'By recrystallizing from dilute methanol, the di-guanylhydrazone of 3,3-di-aldehydo-1,5-di-phenoxypentane having a melting point of C. is obtained as .white crystals. The compound has the following formula:

.butane ;(prepared from 4 hydroxybenzaldehyde and 1,4-

dissolved inabout 1.5 liters of :hot water and the base is ita ted with ammonia. After boiling with methanol,

noxybutane is obtained in white crystals of the decomposition point 255 C. The compound has the following formula:

Example 17 Fourteen grams of p,p'-dialdehydo-l,S-di-phenoxypropanol (2) (prepared from p-hydroxybenzaldehyde and cipitated with ammonia. By recrystallizing from dilute methanol, the di-guanylhydrazone of 4,4'-di-aldehydo- 2,2-di-methoxy-1,5'-di-phenoxypentane is obtained as white crystals having a melting point of 160 C. The compound has the following formula:

1,3-dibromopropanol) are dissolved in 150 cc. of hot alcohol. After addition of 10.3 grams of aminoguanidine Example 18 Twenty-four grams of aminoguanidine hydrochloride, dissolved in 24 cc. of water with the addition of 8 cc. of

concentrated hydrochloric acid, are added to an alcohol 40 Example 19 Fifteen and seven-tenths grams of p,p-di-aldehydo-2,2'- diphenoxy diethylether obtained from p-hydroxybenzaldehyde, p-fl di-chloroethylether and sodium hydroxide solution are dissolved in 900 cc. of hot ethanol. Eleven grams 25 of aminoguanidine chlorohydrate in 11 milliliters of water and 8 milliliters of concentrated hydrochloric acid are added. The mixture is concentrated to about 150 milliliters on the water bath. Upon cooling the di-hydrochloride separates. After recrystallizing from a mixture of methanol and ethanol, yellow crystals with a melting point of 187 C. are obtained. After dissolving in water and precipitation in ammonia, the bisguanylhydrazone of the p,p'-di-aldehydo-2,2'-di-phenoxydiethylether is obtained. The base is very difiicultly soluble and is purified by boiling with ethanol into white crystals, decomposing at 229 C. The compound has the following formula:

solution of the dialdehyde, prepared from 30.4 grams of vanillin and 1,5-dibromo-n-pentane in the presence of caustic alkali, and heated at 70-80 C. for three hours. After cooling, the di-hydrochloride is isolated and dissolved in a large quantity of hot water and the base pre- We claim: 1. As a new chemical compound, a di-guanyl hydrazone of a di-phenoxy di-alkyl ether di-aldehyde, in which the di-alkyl ether portion has from 2 to 12 carbon atoms.

2. As a new chemical compound, the bisguanylhydrazone of p,p-di-aldehydo-2,2-di-phenoxydiethylether.

References Cited in the file of this patent UNITED STATES PATENTS 2,425,223 Barber Aug. 5, 1947 2,584,784 Biswell Feb. 5, 1952 FOREIGN PATENTS 575,145 Great Britain Feb. 5, 1946 OTHER REFERENCES Ruzicka et al.: Helv. Chim. Acta., v01. 27, pp. 1561-9 

1. AS A NEW CHEMICAL COMPOUND A DI-FUANYL HYDRAZONE OF A DI-PHENOXY DIALKYL EHTER DI-ALDEHYDR IN WHICH THE DI-ALKYL ETHER PORTION HAS FORM 2 TO 12 CARBON ATOMS 